CD30 and its ligand, CD30L, are membrane proteins of the TNFR and TNF ligand superfamilies, respectively, and are expressed on various lymphoid and myeloid cells. CD30 was first described as an antigen on Hodgkin's disease cells, and presently is widely used as a clinical marker for a number of hematologic malignancies (for review, see Horie and Watanabe, Immunol 10:457–470 (1998)). A naturally-occurring soluble form of the CD30 protein is found in human serum, and levels of this protein are elevated in a variety of pathological conditions including viral infection, allergic and autoimmune conditions and neoplastic diseases.
CD30 and CD30L are expressed on T cells, and appear to be involved in regulation of the immune system. Their expression on T cells is activation-dependent. CD30 has been reported to be a specific marker of TH2 type T cells (Romagnani, J Leukocyte Biol 57:726 (1995); Romagnani, J Clin Immunol 15:121–129 (1995)). The TH1 and TH2 subsets of CD4+ T cells can be distinguished based on which cytokines they predominantly express. Though individual T cells may actually secrete mixtures of these two groups of cytokines, chronic immune reactions are often dominated by one type or the other of CD4+ T cells. T cells that produce TH2 cytokines, which include IL-4, generally are considered to be mediators of allergic reactions. It has been suggested that the detection of circulating CD30+ T cells could serve as a marker for TH2-dominated allergic conditions such as atopic dermatitis (Yamamoto et al., Allergy 55:1011–18 (2000)); however, the correlation between CD30 expression and TH2 phenotype has not held up over time (see, for example, Bengtsson et al, J Leukocyte Biol 58:683 (1996); Hamann et al., J Immunol 156:1387–91 (1996)). Based on experiments using a mouse model of diabetes, it has been proposed also that CD30-mediated signaling may protect against autoimmune disease (Kurts et al., Nature 398:341–344 (1999)). Others have reported that IL-4 upregulates, whereas IFNγ downregulates, the expression of CD30 on activated T cells (Nakamura et al., J Immunol 158:2090–98 (1997); Gilfillan et al., J Immunol 160:2180–87 (1998)).
The naturally-occurring ligand for CD30, CD30L, is a type II membrane glycoprotein that binds specifically with CD30, thus triggering CD30 to transmit a signal via its cytoplasmic domain. The isolation of mouse and human cDNAs encoding CD30L is described in U.S. Pat. No. 5,480,981. In addition to being expresed on activated T cells, CD30L is expressed on monocytes/macrophages, granulocytes and a subset of B cells (see, for example, U.S. Pat. No. 5,480,981). CD30L has been reported to induce murine B cell differentiation and the proliferation of activated T cells in the presence of an anti-CD3 co-stimulus (see, for example, Smith et al., Cell 73:1349–1360 (1993)). Moreover, it has been reported that CD30L exhibits “reverse signaling,” that is, the cell surface CD30L that is expressed on neutrophils and peripheral blood T cells can be activated by cross-linking to stimulate metabolic activities in those cells (Wiley et al., J Immunol 157: 3235–39 (1996)).
There is a need to better understand the biological activities of CD30 and CD30L, and to exploit this knowledge in the treatment of human disease.